The present invention relates generally to methods and systems for determining the adequacy of treatment during hemodialysis of a patient utilizing a non-invasive near-infrared tissue analysis. More specifically, the invention relates to direct measurement of urea concentrations in tissue of patients undergoing dialysis with light diffusely reflected by skin in conjunction with a spectrographic model, which relates urea concentration to a diffusely reflected light spectrum.
Measurement of the efficacy of hemodialysis treatments is currently time consuming, inaccurate and expensive. Approximately 260,000 Americans suffer from end-stage renal disease (ESRD). Fifty-nine percent are treated by thrice-weekly maintenance hemodialysis sessions designed to clear the products of metabolism that are normally excreted by the kidneys in the urine. Since the failure to adequately dialyze a patient has been shown to increase mortality and morbidity and since the process of dialyzing an ESRD patient is complex and variable in terms of the efficiency of the treatment, a number of methods have been developed to quantify the effectiveness of the treatment. The technique used in the overwhelming majority of dialysis centers is based on pre- and post-dialysis measurements of blood urea nitrogen concentrations. Urea, a low-molecular weight molecule, is a product of protein metabolism that is normally cleared from the body by the kidneys. Because it is also cleared from the blood by the dialysis process and easily measured in blood, its disappearance from the blood during hemodialysis is a measure of the efficacy or adequacy of that particular treatment session. The process of removal of toxins from the body by hemodialysis is best represented as a logarithmic function. As such, the coefficient of the natural logarithm termed KT/Vd, which is calculated from pre- and post-dialysis measurements of blood urea concentrations, can be used as a single descriptor of dialysis adequacy.
The importance of adequate duration or dose of hemodialysis has been underscored recently by the observation that the adjusted mortality of patients with renal disease in the United States exceeds that of several other countries, despite a longer life expectancy of the general population of the United States. A number of studies have documented the failure to deliver an adequate dose of hemodialysis to many Americans. The failure of delivery of adequate hemodialysis doses in the United States is a result of many factors. Time and financial pressures contribute to the problem. Because the metabolic toxins are removed from the blood, which makes up only a fraction of the total volume of the body in which the toxins are distributed, there are delays as the solutes redistribute and equilibrate after dialysis. Thus, measurement of KT/Vd is highly dependent on the time of the urea measurements and the relative size of the compartments such as blood water, interstitial water and intracellular water, all of which harbor urea and other contaminants. These compartments vary in size from patient to patient, and within a patient depending upon present physiologic state. The best measure of the post-dialysis urea is made at least 15 minutes after hemodialysis, but for some patients it may require 50 to 60 minutes to reach equilibrium. There is no accurate way to predict which patients will have a significant blood urea increase following hemodialysis at any given treatment time. Given the time constraints on out-patient hemodialysis centers that commonly are able to dialyze no more than two patients per day on a single machine, one in the morning and one in the afternoon, the need to obtain post-dialysis blood urea concentrations 30 to 60 minutes after dialysis is impractical at best. Finally, the late blood measurement requires an additional venipuncture of the patient who is disconnected from the dialysis machine minutes after cessation of circulation through the machine.
Urea testing is a capital burden on the dialysis centers that provide dialysis to ESRD patients under a capitated reimbursement basis. The blood drawing process is labor intensive and exposes the nursing staff to blood borne pathogens. The samples must then be transported to a laboratory for analysis, incurring another charge and a delay in reported values. Currently, the accepted xe2x80x9cstandard of carexe2x80x9d given financial constraints is that KT/Vd be measured once per month, that is, once during every 12 dialysis sessions. In summary, hemodialysis is xe2x80x9cunder-deliveredxe2x80x9d in the United States. Financial and time constraints result in failure to recognize such inadequacy given the infrequent collection of blood for urea samples and calculation of KT/Vd, as well as poor modeling due to variability of the rebound effect and early post dialysis blood collection.
As noted above, monitoring the adequacy of hemodialysis, as defined by the National Kidney Foundation (NKF)xe2x80x94xe2x80x9c1997 DOQI Clinical Practice Guidelines for Hemodialysis Adequacyxe2x80x9d, and the Renal Physicians Associations (RPA) xe2x80x9c1993 Clinical Practice Guidelines on Adequacy of Hemodialysisxe2x80x9d, entail measuring blood urea nitrogen (BUN) pre- and post-dialysis once per month in order to calculate the so-called single pool KT/Vd value with K=dialyzer clearance, T=time of dialysis, and V=volume of distribution of urea. KT/Vd is then calculated from pre- and post-dialysis BUN concentrations by the following formula:
KT/V=xe2x88x92Ln(Ct/Coxe2x88x920.008txe2x88x92UF/W)
Where Ct is the post-dialysis urea level and Co is the pre-dialysis urea level; t is the time; UF is the ultrafiltrate removed; and W is the post-dialysis weight.
The equation is most representative of the true dialysis dose if the post session BUN blood sample is drawn after the blood urea has equilibrated with the interstitial and intracellular urea. Release of sequestered urea from the intracellular space to the extracellular space continues for 30 to 60 minutes after completion of a dialysis session. This equilibration is due to the removal of urea from the blood by the dialyzer at a rate that exceeds the rate of diffusion from the intracellular to the extracellular compartment. Delays of equilibrium are also caused by the so-called xe2x80x9cflow-volume disequilibriumxe2x80x9d. Seventy percent of the total body water is contained in organs that receive only 20% of the cardiac output. Relatively poorly perfused tissues such as skin, muscle, and bone are cleared of urea less efficiently than highly vascularized organs such as the liver or lungs. The consequence of this compartmentalization of urea is an increase in the BUN concentration over the 60 minutes after the completion of hemodialysis.
The magnitude of the urea rebound varies greatly among dialysis patients. The average increase of urea concentration in the 30 minutes following completion of dialysis is 17%. However, some patients exhibit a rebound as high as 45%. This results in a 75% error between KT/V based on immediate post-dialysis BUN measurement and 30 minutes post-dialysis determination. Despite these limitations of the single-pool KT/V model based on the immediate post-dialysis BUN, the need to obtain the post-dialysis BUN sample 30 to 60 minutes after the completion of dialysis in order to compute the more accurate double-pool KT/V, is impractical in the out-patient hemodialysis setting.
At least two methods for approximating the equilibrated or double-pool KT/Vd have been proposed in the literature. The Smye formula approximates the equilibration BUN concentration based on three urea measurements, the usual pre- and post-dialysis determinations, as well as a mid-dialysis blood sample. This method yields an average error of 13% between the estimated equilibration KT/V and the true equilibrated value. The Daugirdas formulas are based on linear transformations of the single-pool KT/V modified according to the type of vascular access; venous shunt or arterial shunt. The improvement of accuracy is comparable to the Smye method.
Despite limitations of the single pool technique, the NKF recommends its use because of the impracticality of the late measurement of urea in the out-patient setting and the unproven accuracy of the double pool estimates.
Living human tissue and blood is recognized as a dynamic system containing a multitude of components and analyte information that is particularly useful in the medical profession for diagnosing, treating and monitoring human physical conditions. To this end, effort has been directed toward developing methods for non-invasive measurement of tissue and blood constituents using spectroscopy. The spectrographic analysis of living tissue has been focused on the identification of spectral information that defines individual analytes and relating such spectral data to the analyte""s concentration. Concentration of these analytes vary with time in an individual patient. Acquiring tissue spectral data with sufficient accuracy for use in diagnosis and treatment has proven difficult. Difficulties in conducting the analysis have been found, which are related to the fact that the tissue system is a complex matrix of materials with differing refractive indices and absorption properties. Further, because the constituents of interest are many times present at very low concentrations, high concentration constituents, such as water, have had a detrimental impact on identifying the low level constituent spectral information and giving an accurate reading of the desired constituent concentration.
Improved methods and apparatus for gathering and analyzing a near-infrared tissue spectra for an analyte concentration are disclosed in commonly assigned U.S. Patent applications and issued patents. U.S. Pat. No. 5,655,530 and U.S. patent application Ser. No. 08/844,501, filed Apr. 18, 1997, entitled xe2x80x9cMethod for Non-invasive Blood Analyte Measurement with Improved Optical Interfacexe2x80x9d relate to near-infrared analysis of a tissue analyte concentration which varies with time, with a primary focus on glucose concentrations in diabetic individuals. The methods and apparatus include placing a refractive index-matching medium between a sensor and the skin to improve the accuracy and repeatability of testing. U.S. patent application Ser. No. 09/174,812, filed Oct. 19, 1998, entitled xe2x80x9cMethod for Non-Invasive Blood Analyte Measurement with Improved Optical Interfacexe2x80x9d discloses additional improvements in non-invasive living tissue analyte analysis. The disclosure of each of these three applications or patents are hereby incorporated by reference.
U.S. Pat. No. 5,636,633 relates, in part, to another aspect of accurate non-invasive measurement of an analyte concentration. The apparatus includes a device having transparent and reflective quadrants for separating diffuse reflected light from specular reflected light. Incident light projected into the skin results in specular and diffuse reflected light coming back from the skin. Specular reflected light has little or no useful information and is preferably removed prior to collection. U.S. patent application Ser. No. 08/871,366, filed Jun. 9, 1997 now Pat. No. 5,935,062 , entitled xe2x80x9cImproved Diffuse Reflectance Monitoring Apparatusxe2x80x9d, discloses a further improvement for accurate analyte concentration analysis which includes a blocking blade device for separating diffuse reflected light from specular reflected light. The blade allows light from the deeper, inner dermis layer to be captured, rejecting light from the surface, epidermis layer, where the epidermis layer has much less analyte information than the inner dermis layer, and contributes noise. The blade traps specular reflections as well as diffuse reflections from the epidermis. The disclosures of the above patent and application, which are assigned to the assignee of the present application, are also incorporated herein by reference.
The present invention is directed to a method and apparatus to directly measure the urea concentration of patients undergoing dialysis, using reflectance, non-invasive near-infrared (NIR) spectroscopy. Thus, instead of drawing blood samples from the patient at the beginning and end of dialysis for analysis of BUN concentrations at a clinical laboratory, the patient""s skin will be xe2x80x9cscannedxe2x80x9d and BUN concentration determined in real-time. This will allow the calculation of dialysis dose or KT/Vd to be measured and reported by the end of the dialysis session.
In its broadest sense, the present invention includes a method for assessing the need for hemodialysis, the progress of a hemodialysis procedure or the adequacy of a hemodialysis treatment. The method generally includes providing a means for optical analysis of tissue on a patient with the means for optical analysis providing an output spectrum at multiple wavelengths. Tissue, as defined herein, includes all tissue components found in a given cross section that is optically penetrated during analysis. The tissue is chiefly made up of extravascular water, which includes both interstitial and intracellular fluid, with a relatively small fraction comprising blood. The output spectrum has varying intensities as related to absorption by the non-vascular tissue. The tissue is coupled to the means for optical analysis, and an output spectrum is acquired before, during or after hemodialysis. The tissue urea concentration, in contrast to blood urea concentration, is calculated from a mathematical model relating the output spectrum to the tissue urea concentration.
In the most limited case, the method and apparatus of the present invention would be used in dialysis centers to measure the pre- and post-dialysis urea levels of patients for real-time KT/V calculations. In a preferred method, measurement can also be made continuously for more detailed urea removal modeling or for feedback to the dialysis unit for feedback and control purposes.
The advantages of the method of the present invention over the standard method of calculation of KT/V by pre- and post-dialysis blood sample BUN measurement are four-fold. First, the accuracy of the calculation of KT/V measured at the end of dialysis approaches the accuracy of KT/V based on post equilibrium blood sample BUN measurements. This is due to the fact that the analysis is of tissue versus blood. The tissue has a relatively small (and negative) urea rebound. Because the tissue water is both chiefly extravascular and much of it is relatively poorly vascularized, its urea content more closely correlates with equilibrated total body urea and equilibrated blood sample BUN than does the immediate post-dialysis, pre-rebound blood sample BUN. Thus, the non-invasive skin measurement of urea delivers the accuracy of the equilibrated or two-pool KT/V, but does not require that the dialysis patient and staff wait 30 minutes or more after dialysis before collecting a final blood sample.
Second, calculation of KT/V is nearly xe2x80x9creal-timexe2x80x9d. The clinician or staff overseeing the dialysis session will be able to judge the efficacy or adequacy of the dialysis dose at the time it is delivered in a xe2x80x9cpoint of carexe2x80x9d mode. Failure to deliver the prescribed dose can be appreciated before the patient leaves the dialysis clinic. A decision can then be made to continue the current session or adjust the following dialysis session dose. Should the machine be devoted to a single patient during dialysis, true, real-time kinetic modeling is possible.
Third, the non-invasive nature of the measurement limits the exposure of nursing and technical staff to blood born infectious agents. Two blood samples must be removed from the closed loop hemodialysis circuit and transferred to standard blood analysis tubes in order to calculate the KT/V. In an average hemodialysis centers, where 100 clients are dialyzed, at least 200 blood samples are drawn and sent via courier to a clinical chemistry laboratory. Replacement of blood sample BUN measurements by non-invasive skin measurements would substantially reduce the potential of infection of both the nursing staff who draw blood samples and laboratory personnel who then handle the specimens.
Finally, a fourth advantage over the current methods is a reduction of the cost per measurement. Although the investment in such a device will have to be considered in terms of the fixed reimbursement for monthly measures of KT/V, the clinician will not incur significant costs by using the device more often than once per month. In fact, like the usual blood pressure measurement at the end of a dialysis session, a non-invasive measure of urea would require no reoccurring costs except the time to make the measurement. Dialysis patients would greatly benefit from more frequent measurement of the dialysis dose.
Success of the method of the present invention is believed tied to two components. First, the method incorporates an apparatus and technique for accurately and repeatably acquiring a tissue spectra which is both stable and sensitive to slight changes in spectral output at desired wavelengths and optimizes optical throughput both into and out of the tissue sample. Second, because the spectral features, which can be correlated to tissue urea concentration are not readily apparent from the spectral data, a mathematical model is utilized to correlate spectral data to a tissue urea concentration. The model is built based on multiple tissue scans and same time blood sample BUN measurements. The method preferably incorporates a resultant mathematical model based on Partial Least Squares Algorithm applied to the multiple tissue scans and concomitant BUN measurements which is then applied to an unknown spectra.
The present invention, thus, includes a method for measuring tissue urea concentration of an individual before, during or just after hemodialysis using non-invasive tissue spectroscopy. A preferred method and apparatus illuminates skin with near infrared radiation and collects the reflected, non-absorbed near infrared radiation. Diffuse, rather than specular, reflected light is preferably collected, more preferably light diffusely reflected from the inner dermis rather than the epidermis. For illustrative purposes, three methods are set forth for capturing light diffusely reflected from the inner dermis, including a blocker blade, use of blocking and free zones in a lens or mirror surface, and use of an index matching medium to coat tissue. The near infrared spectra collected can be stored in a computer database.
The method for non-invasively measuring the concentration of urea in tissue includes first providing an apparatus for measuring infrared absorption by a urea containing tissue. The apparatus includes generally three elements, an energy source, a sensor element, and a spectrum analyzer. The sensor element includes an input element and an output element. The input element is operatively connected to the energy source by a first means for transmitting infrared energy. The output element is operatively connected to the spectrum analyzer by a second means for transmitting infrared energy.
In preferred embodiments, the input element and output element comprise lens systems which focus the infrared light energy to and from the sample. In a preferred embodiment, the input element and output element comprise a single lens system which is utilized for both input of infrared light energy from the energy source and output of both specular and diffusely reflected light energy from the analyte-containing sample. Alternatively, the input element and output element can comprise two lens systems, placed on opposing sides of an analyte-containing sample, wherein light energy from the energy source is transmitted to the input element and light energy transmitted through the urea-containing sample then passes through the output element to the spectrum analyzer.
The first means for transmitting infrared energy, in preferred embodiments, simply includes placing the infrared energy source proximate to the input element so that light energy from the source is transmitted via the air to the input element. Further, in preferred embodiments, the second means for transmitting infrared energy preferably includes a single mirror or system of mirrors which direct the light energy exiting the output element through the air to the spectrum analyzer.
In practicing the method of the present invention, a urea-containing tissue area is selected as the point of analysis. This area can include the skin surface on the finger, earlobe, forearm or any other skin surface. Preferably, the urea-containing tissue is the underside of the forearm.
A quantity of an index-matching medium or fluid is then placed on the skin area to be analyzed. The index-matching fluid detailed herein is selected to optimize introduction of light into the tissue, reduce specular light and effectively get light out of the tissue. The medium or fluid preferably contains an additive which confirm proper coupling to the skin surface by a proper fluid, thus assuring the integrity of test data. It is preferred that the index-matching medium is non-toxic and has a spectral signature in the near-infrared region which is minimal, and is thus minimally absorbing of light energy having wavelengths relevant to the urea being measured. In preferred embodiments, the index-matching medium has a refractive index of about 1.38. Further, the refractive index of the medium is preferably constant throughout the composition.
The sensor element, which includes the input element and the output element, is then placed in contact with the index-matching medium. In this way, the input element and output element are coupled to the urea-containing tissue or skin surface via the index-matching medium which eliminates the need for the light energy to propagate through air or pockets of air due to irregularities in the skin surface.
In analyzing for the concentration of urea in the tissue, light energy from the energy source is transmitted via the first means for transmitting infrared energy into the input element. The light energy is transmitted from the input element through the index-matching medium to the skin surface. Some of the light energy contacting the analyte-containing sample is differentially absorbed by the various components and analytes contained therein at various depths within the sample. Some of the light energy is also transmitted through the sample. However, a quantity of light energy is reflected back to the output element. In a preferred embodiment, the non-absorbed or non-transmitted light energy is reflected back to the output element upon propagating through the index-matching medium. This reflected light energy includes both diffusely reflected light energy and specularly reflected light energy. Specularly reflected light energy is that which reflects from the surface of the sample and contains little or no analyte information, while diffusely reflected light energy is that which reflects from deeper within the sample, wherein the analytes are present.
In preferred embodiments, the specularly reflected light energy is separated from the diffusely reflected light energy. The non-absorbed diffusely reflected light energy is then transmitted via the second means for transmitting infrared energy to the spectrum analyzer. As detailed below, the spectrum analyzer preferably utilizes a computer to generate a urea concentration utilizing the measured intensities, a calibration model, and a multivariate algorithm.
The computer includes a memory having stored therein a multivariate calibration model empirically relating the known urea concentration in a set of calibration samples to the measure intensity variations from the calibration samples, at several wavelengths. Such a model is constructed using techniques known by statisticians.
The computer predicts the analyte concentration of the urea-containing sample by utilizing the measure intensity variations, calibration model and a multivariate algorithm. Preferably, the computation is made by the partial least square technique as disclosed by Robinson et al. in U.S. Pat. No. 4,975,581, incorporated herein by reference.
These and various other advantages and features of novelty which characterize the present invention are pointed out with particularity in the claims annexed hereto and forming a part hereof. However, for a better understanding of the invention, its advantages, and the object obtained by its use, reference should be made to the drawings which form a further part hereof, and to the accompanying descriptive matter in which there are illustrated and described preferred embodiments of the present invention.